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See detailTraining alters the innate immune response in the lower airway of horses
Frellstedt, Linda ULg

Doctoral thesis (2014)

Many human and animal studies have examined various markers of the innate and/or adaptive immunity in association with exercise and have come to the general conclusion that exercise, either acute or ... [more ▼]

Many human and animal studies have examined various markers of the innate and/or adaptive immunity in association with exercise and have come to the general conclusion that exercise, either acute or chronic, modifies the immune response. Regular moderate exercise has beneficial and protective effects on immunity because it results in a balance of pro- and anti-inflammatory effects. This balance may be disturbed during exhaustive exercise, such as that experienced during competition and overtraining, resulting in immunosuppression. Humans frequently suffer from upper respiratory tract infections after prolonged intense exercise, whereas horses suffer primarily from lower airway inflammation and/or infection. The underlying mechanism for this difference remains unknown at this time. The sampling of different cell types is limited in humans and therefore, these studies focus on the evaluation of cells in peripheral blood or markers in saliva. Two groups of researchers in human sports medicine have compared populations of sedentary and regularly exercising people. The expression of Toll-like receptors (TLRs) 1, 2, 3 and 4 was decreased in peripheral blood monocytes in exercising subjects. This altered expression of TLRs was also associated with a lower production of pro-inflammatory cytokines (IL-6, IL-1α, TNF-α). Regular exercise induced circulating anti-inflammatory cytokines (IL-10, IL-6) and, therefore, limited the effects of pro-inflammatory cytokines. The first line of defense in the airways is provided by pulmonary alveolar macrophages and bronchial epithelial cells. Strenuous exercise impairs the viability of bronchial epithelial cells, reduces the viral defense mechanisms, and decreases oxidative burst activity of pulmonary alveolar macrophages. The altered immune response in association with exercise/training does not only lead to an increased risk for infection but may also cause the development of allergies and chronic inflammation in the lower airway. This may explain why young equine athletes frequently suffer from Inflammatory Airway Disease (IAD). The etiology of IAD remains unknown but an association with subclinical viral infections as well as inflammatory stimuli from the environment has been suspected. The objective of this work was to increase our knowledge of immune mechanisms in young equine athletes by evaluating the effect of acute exercise and training on the innate immune responses of pulmonary alveolar macrophages (PAM), bronchial epithelial cells (BEC) and monocytes. The hypothesis was that exercise and training modify the TLR mRNA expression as well as the production of pro-inflammatory cytokines and interferons in these three cell types. Eight Standardbred horses were studied over a period of 9 months during which they were acclimatized, trained and deconditioned. Standardized exercise tests were performed regularly and biological samples (blood, bronchoalveolar lavages, and biopsies of the bronchial epithelium) were taken at defined intervals in order to allow a longitudinal evaluation of the different parameters. Monocytes, PAM and BEC were harvested and analyzed. The expression of TLR3 was decreased in equine PAM and monocytes after a period of training, but not after a single strenuous exercise session. In addition, the expression of TLR4 was increased in equine monocytes after training. The production of TNF-α and IFN-β was also examined in PAM and monocytes ex vivo after the stimulation with different TLR ligands. The production of these cytokines was reduced in PAM after a defined period of training and remained decreased for three months thereafter. In contrast, the synthesis of TNF-α was increased after a period of training in equine monocytes and remained increased thereafter. In a second study, a model for the culture of equine bronchial epithelial cells (EBEC) was developed which allowed us to evaluate the effect of exercise and training on the innate immune response of these cells. Acute exercise or training did not alter the TLR mRNA expression in EBEC. The production of IFN-β was increased in EBEC from trained horses after stimulation with a TLR3 ligand. Concurrently, the secretion of TNF-α and IL-6 was impaired in EBEC from trained horses after the stimulation with TLR2 and TLR3 ligands. This study focused on a single aspect of the innate immunity in horses, gaining knowledge of the TLR expression in three cell types and their response to specific TLR agonists. These results have to be considered in the global context of the innate immunity remembering that they represent only a small part of the complex immune system. Only one type of training (Standardbred race training) and one model of acute exercise (standardized exercise test on a treadmill) were evaluated in this study. This should be considered when drawing conclusions, because it is currently understood that the effects on immune responses vary with different types, intensity and duration of exercise and/or training. Nonetheless, this work has established that a local immunosuppression develops within the lungs in trained horses, and may explain the increased susceptibility of exercising horses to pulmonary viral infections. This local immunosuppression is associated with an increased potential of monocytes to produce pro-inflammatory cytokines when challenged with pathogens. The effects of exercise on innate immunity are complex and further studies are needed to continue the work in this field. In addition to the response to training in young sport horses, a number of environmental factors associated with their nutrition and housing may play important roles in the development of pulmonary infections and inflammation (e.g. IAD). To confirm the significance of the presented results, it would be interesting to investigate the innate immune response in trained horses when challenged with equine pathogens, such as equine influenza and equine herpesviruses. The ultimate goal of this work and other studies in the future is to develop immuno-modulating molecules that could be used for the prevention and treatment of equine respiratory diseases. [less ▲]

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See detailTraining Modifies Innate Immune Responses in Blood Monocytes and in Pulmonary Alveolar Macrophages
Frellstedt, Linda ULg; Waldschmidt, Ingrid; Gosset, Philippe et al

in American Journal of Respiratory Cell and Molecular Biology (2014), 51(1), 135-142

In humans, strenuous exercise causes increased susceptibility to respiratory infections associated with down-regulated expression of Toll-like receptors (TLRs), co-stimulatory and antigen-presenting ... [more ▼]

In humans, strenuous exercise causes increased susceptibility to respiratory infections associated with down-regulated expression of Toll-like receptors (TLRs), co-stimulatory and antigen-presenting molecules. Lower airway diseases are also a common problem in sport and racing horses. Because the innate immunity plays an essential role in lung defense mechanisms, we aimed to assess the effect of acute exercise and training on innate immune responses in two different compartments. Blood monocytes and pulmonary alveolar macrophages (PAM) were collected from horses in an untrained, moderately and intensively trained as well as deconditioned state before and after a strenuous exercise test (SET). The cells were analysed for TLR mRNA expression by real-time PCR in vitro and the cytokine production after in vitro stimulation with TLR ligands was measured by ELISA. Our results showed that training, but not acute exercise, modified the innate immune responses in both compartments. The mRNA expression of TLR3 was down-regulated by training in both cell types, whereas the expression of TLR4 was up-regulated in monocytes. Monocytes treated with lipopolysaccharide (LPS) and a synthetic diacylated lipoprotein (FSL) showed increased cytokine secretion in trained and deconditioned subjects indicating the activation of cells at the systemic level. The production of TNF-alpha and IFN-beta in non-stimulated and stimulated PAM was decreased in trained and deconditioned horses and might therefore explain the increased susceptibility to respiratory infections. Our study reports a dissociation between the systemic and the lung response to training that is probably implicated in the systemic inflammation and in the pulmonary susceptibility to infection. [less ▲]

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See detailTraining modifies the innate immune response both in the airways and in blood in horses
Frellstedt, Linda ULg; Gosset, Philippe; Desmet, Christophe ULg et al

in Proceedings of the ICI (2013)

Lower airway diseases are common problems in sports and racing horses. In humans, exercise has been associated with upper respiratory tract infections due to down-regulated expression of Toll-like ... [more ▼]

Lower airway diseases are common problems in sports and racing horses. In humans, exercise has been associated with upper respiratory tract infections due to down-regulated expression of Toll-like receptors (TLRs), costimulatory and antigen-presenting molecules on monocytes. The objectives of this study were 1) to examine the expression of TLRs in equine bronchial epithelial cells (EBEC) and blood monocytes in untrained and trained horses; 2) to stimulate EBEC and monocytes in vitro with TLR ligands, in order to mimic bacterial/viral infections; 3) to compare the cytokine production of EBEC and monocytes in untrained and trained horses. Bronchial biopsies were taken from 8 horses during lower airway endoscopy at rest and 24 hours after a standardized exercise test (SET). Bronchial epithelial cells were grown in vitro and activated with TLR ligands. Blood monocytes were collected at rest and after the SET. TLR1-TLR9 expression was evaluated via real-time PCR and cytokine production was measured via ELISA. TLR3 and TLR4 expression was modified by training. The expression of TLR2, TLR7 and TLR8 was modified only by strenuous exercise in trained horses. Training had local immuno-suppressive effects shown by a decreased production of TNF-alpha and IFN-beta in EBEC in response to TLR2 and TLR3 ligands. Training also caused a systemic pro-inflammatory response evidenced by increased production of TNF-alpha in monocytes in response to TLR2 and TLR4 ligands. These findings suggest that training and strenuous exercise in trained subjects may result in an increased susceptibility of the lower airway to infections associated with systemic inflammation. [less ▲]

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See detailExercise modifies the innate immune response in equine bronchial epithelial cells
Frellstedt, Linda ULg; Gosset, Philippe; Pirottin, Dimitri ULg et al

in Proceedings of the 3rd Scientific Meeting of the Faculty of Veterinary Medicine (University of Liege - Belgium) (2013)

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See detailTraining-induced decrease of cytokines production by equine alveolar macrophages
Waldschmidt, Ingrid ULg; Frellstedt, Linda ULg; Art, Tatiana ULg et al

in Proceedings of the 6th Congress of the European College of Equine Internal Medicine (ECEIM) (2013)

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See detailInvestigation of the effect of exercise on the innate immunity in horses
Frellstedt, Linda ULg; Gosset, Philippe; Desmet, Christophe ULg et al

Poster (2012, October 19)

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See detailMethacholine bronchoprovocation test:a useful ancillary test for diagnosis of hyperresponsiveness in horses ?
Frippiat, Thibault ULg; Frellstedt, Linda ULg; Bustin, Jean-Clément ULg et al

in Proceedings of the European Veterinary Conference - Voorjaarsdagen (2012)

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See detailLes tests de bronchoprovocation à la métacholine dans le diagnostic de l'hyperréactivité bronchique chez le cheval asymptomatique
Frippiat, Thibault ULg; Frellstedt, Linda ULg; Bustin, Jean-Clément ULg et al

in Proceedings de la 38ème Journée de la Recherche Equine (2012)

The clinical examination and the ancillary tests at the disposal from the veterinarian may be poor diagnostics in horses suffering from subclinical inflammatory airway disease or in clinical remission of ... [more ▼]

The clinical examination and the ancillary tests at the disposal from the veterinarian may be poor diagnostics in horses suffering from subclinical inflammatory airway disease or in clinical remission of recurrent airway obstruction (RAO). The objective of this study was to determine whether the methacholine bronchoprovocation test -which is daily used for diagnosis of asymptomatic human asthma- may be used as an applicable and repeatable method for the diagnosis of an increased susceptibility to bronchospasm in horses. The test, realised on 8 horses (6 with RAO history and 2 controls) presents a good feasibility and significant repeatability. Dust exposure increased the bronchoreactivity, while it did not affect other clinical and functional parameters or inflammatory markers. In the future, the bronchoprovocation test could therefore find its place in clinicat practice for the detection of asymptomatic horses which are susceptible to develop bronchospasm in poor environmental conditions. [less ▲]

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See detailInvestigation of the innate immunity in the lower respiratory tract in exercising horses
Frellstedt, Linda ULg; Gosset, Philippe; Desmet, Christophe ULg et al

in Proceedings of the 1st Scientific Meeting of the Faculty of Veterinary Medicine (2011)

Detailed reference viewed: 37 (8 ULg)